Sudden cardiac arrest (SCA) is a major public health concern, accounting for up to 400,000 annual deaths in the US alone. Although a variety of molecular pathways, electrophysiologic characteristics, and pathologic conditions can result in SCA, clinical and autopsy studies have consistently demonstrated a predominant, common pathophysiology in Western populations. The most common electrophysiologic mechanism for SCA is ventricular fibrillation and the most common pathologic substrate is coronary artery disease (CAD). Despite recent progress in treatment and prevention of CAD, SCA continues to be one of the leading causes of mortality. There are few effective approaches to SCA prevention for the general population and equally few clues to identify individuals predisposed to life-threatening arrhythmias. Identifying those at increased risk, and discovering novel therapeutic targets for arrhythmia prevention and treatment is of great public health importance. Epoxyeicsatrienoic acids (EETs) are important signaling lipid metabolites of arachidonic acid mediated by cytochrome P450 (CYP) enzymes. EETs have electrophysiological significance in regulating L-type Ca2+, Na+ and ATP dependent K+ (KATP) channels that maintain a normal QT-period and reduce the prolonged QT period following ischemia reperfusion injury. They also protect against ventricular tachyarrhythmia during cardiac hypertrophy. In humans CYP2J2 is the main enzyme responsible for EET biosynthesis in cardiac tissue. CYP2J2 is differentially regulated in various cell types and decline in expression or activity results in lower EETs in cardiomyocytes, which can lead to toxicity. We discovered that circulating EETs in erythrocytes were significantly correlated with cardiac tissue EETs in mice. In addition, erythrocyte EETs were significantly lower in SCA patients than controls. This research project aims to test the hypothesis that EETs protect cardiac tissue from ischemic injury as well as lethal ischemia-triggered arrhythmias. We also hypothesize that lower EETs in circulating plasma or erythrocyte membranes are associated with higher risk of SCA. These hypotheses will be tested in three aims as follows; Aim 1 will determine the risk associated with SCA and circulating EETs in plasma and RBC membranes in a large sample of SCA patients and controls. Aim 2 will determine the molecular mechanism for EETs' protective effect during prolonged ischemia and ischemia potentiated arrhythmias in a transgenic mouse model expressing human CYP2J2 in cardiac tissue vs. wild type mice. Aim 3 will test the role of CYP2J2 down regulation in cardiomyocyte dysfunction during ischemic stress and for the first time, determine the genomic pathways associated with the expression of CYP2J2 in ventricular myocytes. These aims together will aid in developing new clinical strategies to combat SCA by improved risk stratification and identification of novel drug targets for treatment and prevention.